Diabetes mellitus type 2 is a metabolic disorder that is characterized by high blood glucose in the context of insulin resistance (IR) and relative insulin deficiency. Type 2 diabetes makes up about 90% of cases of diabetes and is predominantly thought to be caused by obesity, which results from a sustained imbalance between energy intake and expenditure. It is estimated that more than one-third of the U.S. adult population over 20 years of age had the insulin resistance syndrome in the year 2000, and therefore are at high risk for the development of type 2 diabetes and cardiovascular disease (Ford ES. “Prevalence of the metabolic syndrome defined by the International Diabetes Federation among adults in the U.S.” Diabetes Care 28:2745-2749, 2005).
Type 2 diabetes is initially treated by and dietary modifications and increased exercise. If blood glucose levels are not lowered to an adequately level, patients are usually treated with a number of standard medications such as metformin, an oral antidiabetic drug in the biguanide class. Metformin needs to be regulated to individual patient requirements and in rare cases, metformin can cause lactic acidosis. All patients do not respond to metformin and it is not given to patients with renal insufficiency. For patients who do not respond to metformin, thiazolidinediones are given to improve glucose uptake and blood lipid profile. However, thiazolidinedione treatment has been connected to increased mortality in large prospective studies, why thiazolidinediones are now prescribed with great care.
Many tissues, including the liver, skeletal muscle, and adipocytes, manifest resistance to insulin (Groop L C et.al. “Role of free fatty acids and insulin in determining free fatty acid and lipid oxidation in man”. J Clin Invest 87:83-89, 1991). Although in many individuals the insulin resistance develops simultaneously in multiple organs, the severity of insulin resistance may differ among the various tissues. Present medications don't target a specific tissue, but insulin resistance in general. Subjects suffering from insulin resistance, wherein the insulin resistance is more prominent in on type of tissue would benefit from treatment targeting this tissue. While present medications don't target a specific tissue, present methods allows for quantification of organs which are resistant to insulin, as well as quantification of the magnitude of insulin resistance in each organ.
Glucose metabolism in controlled by a complex interplay of metabolically active tissues. Glucose is taken up by muscles in a process which is mediated by insulin. When muscle tissue is insulin-resistant, glucose uptake decreases, leading to higher blood glucose. The fat tissue stores lipids from the blood, in a process that is also regulated by insulin. Finally, the liver plays an important role in the regulation of blood glucose by regulating glucose production. Insulin inhibits glucose production from the liver. Hence, if the liver is insulin-resistant, glucose production will not be appropriately inhibited after a meal, contributing to high blood glucose.
It has been shown that some patients with type 2 diabetes have primarily perturbations in muscle insulin sensitivity, while hepatic insulin resistance is predominant in other patients (Shulman, G. I. (2000). “Cellular mechanisms of insulin resistance”. J. Clin. Invest. 106, 171-176.; Jornayvaz and Shulman, “Diacylglycerol Activation of Protein Kinase Ce and Hepatic Insulin Resistance”, Cell 2012 15: 574-; Björnholm and Zierath. “Insulin signal transduction in human skeletal muscle: identifying the defects in Type II diabetes”. Biochemical Society Transactions (2005) Volume 33, part 2).
As only some patients with type 2 diabetes suffer from predominant hepatic insulin resistance, a medication targeting insulin resistance in the liver would be of specific interest.
Thus, there is a need for a new treatment for treating or reducing insulin resistance of the liver. Preferably, such treatment should have limited side effects. Also, such treatment should preferably be safely used in combination with other drugs that are in common use in insulin resistant patients, such as antidiabetic drugs, antihypertensive drugs, cholesterol-reducing agents, and insulin.